Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE159655 | GEO | 2021/10/04
REPOSITORIES: GEO
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Project description:We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma versus healthy controls. We identified 119 differentially methylated regions (DMRs) and 118 differentially methylated probes (DMPs) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. Hypo- and hypermethylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma. case control design with nasal epithelial cells from 36 atopic asthmatic and 33 nonatopic nonasthmatic children from the inner city
2015-11-01 | E-GEOD-65204 | biostudies-arrayexpress
Project description:Background: Psoriasis is a T cell-mediated chronic autoimmune/inflammatory disease. While some patients experience disease limited to the skin (skin psoriasis), others develop joint involvement (psoriatic arthritis; PsA). In the absence of disease- and/or outcome-specific biomarkers, and as arthritis can precede skin manifestations, diagnostic and therapeutic delays are common and contribute to disease burden and damage accrual. Objective: Altered epigenetic marks, including DNA methylation, contribute to effector T cell phenotypes and altered cytokine expression in autoimmune/inflammatory diseases. This project aimed at the identification of disease-/outcome-specific DNA methylation signatures in CD8+ T cells from patients with psoriasis and PsA as compared to heathy controls. Method: Peripheral blood CD8+ T cells from 9 healthy controls, 10 psoriasis and 7 PsA patients were collected to analyze DNA methylation marks using Illumina Human Methylation EPIC BeadChips (>850,000 CpGs per sample). Bioinformatic analysis was performed using R (minfi, limma, ChAMP and DMRcate packages). Results: DNA methylation profiles in CD8+ T cells differentiate healthy controls from psoriasis patients (397 Differentially Methylated Positions (DMPs); 9 Differentially Methylated Regions (DMRs) when ≥CpGs per DMR were considered; 2 DMRs for ≥10 CpGs). Furthermore, patients with skin psoriasis can be discriminated from PsA patients (1861 DMPs, 20 DMRs (≥5 CpGs per region), 4 DMRs (≥10 CpGs per region)). Gene ontology (GO) analyses considering genes with ≥1 DMP in their promoter delivered methylation defects in skin psoriasis and PsA primarily affecting the BMP signaling pathway and endopeptidase regulator activity, respectively. GO analysis of genes associated with DMRs between skin psoriasis and PsA demonstrated an enrichment of GABAergic neuron and cortex neuron development pathways. Treatment with cytokine blockers associated with DNA methylation changes (2372 DMPs; 1907 DMPs within promoters, 7 DMRs (≥5CpG per regions)) affecting transforming growth factor beta receptor and transmembrane receptor protein serine/threonine kinase signaling pathways. Lastly, a methylation score including TNF and IL-17 pathway associated DMPs inverse correlates with skin disease activity scores (PASI). Conclusion: Patients with skin psoriasis exhibit DNA methylation patterns in CD8+ T cells that allow differentiation from PsA patients and healthy individuals, and reflect clinical activity of skin disease. Thus, DNA methylation profiling promises potential as diagnostic and prognostic tool to be used for molecular patient stratification towards individualized treatment. This project aimed at the identification of disease-/outcome-specific DNA methylation signatures in CD8+ T cells from patients with psoriasis and PsA as compared to heathy controls.
2021-09-22 | GSE184500 | GEO
Project description:NSAID-exacerbated respiratory disease (N-ERD) represents a particularly severe endotype of chronic rhinosinusitis with nasal polyps (CRSwNP), which affects around 10-16% of CRSwNP patients. N-ERD is characterized by severe and refractory nasal polyposis, bronchial asthma and intolerance to non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. Today, the pathogenesis of AERD remains incompletely understood and curative treatments are lacking. Macrophages are important source and target cells of arachidonic acid metabolites during type 2 inflammation, that have been neglected in N-ERD pathogenesis despite their presence in the nasal mucosa of N-ERD patients. Using a genome-wide methylomics approach, we identified persistent differences in monocytes and alveolar-like monocyte-derived macrophages (aMDM) between N-ERD patients and healthy controls. These were correlated with differentially expressed genes (DEGs) results from our whole transcriptome (RNAseq) analysis, available at: E-MTAB-7965 We isolated monocytes from venous blood and compared them to 7-days in vitro-differentiated aMDM. Cells were lysed in RLT buffer with 1% beta-mercaptoethanol and stored at -80°C until genomic DNA isolation and genome-wide methylomics analysis. Three data analyses were performed. Analyses 1 and 2 compared differentially methylated positions (DMPs) and regions (DMRs) between N-ERD and healthy monocytes or aMDM, respectively. Analysis 3 compared the N-ERD vs. healthy-specific differences between both cell types.
2020-07-31 | E-MTAB-8065 | biostudies-arrayexpress
Project description:Background: Nasal epithelia are emerging as a proxy measure of gene expression of the airway epithelium in asthma. We hypothesized that epigenetic marks regulate gene expression of the nasal epithelia and consequently may provide a novel target for allergic asthma. Methods: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma [N=36] versus healthy controls [N=36]. Results were validated in an independent population of asthmatics [N=30]. Results: We identified 186 genes with significant methylation changes, either as regions (differentially methylated regions [DMRs]) or single CpGs (differentially methylated probes [DMPs]) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. The methylation changes are large (median 9.5%, range: 2.6-29.5% methylation change) and similar in magnitude to those observed in malignancies. Hypo- and hyper-methylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma. Conclusions: Our findings that epigenetic marks in respiratory epithelia are associated with allergic asthma in inner-city children provide new targets for biomarker development, and novel approaches to understanding disease pathogenesis. case control design with nasal epithelial cells from 36 atopic asthmatic and 36 nonatopic nonasthmatic children from the inner city
2015-11-01 | E-GEOD-65163 | biostudies-arrayexpress
Project description:Epigenetic (N=15) were based on the Illumina Infinium HumanMethylation450 BeadChip. We searched for differentially methylated probes (DMPs) and regions (DMRs).
2018-03-19 | GSE107211 | GEO
Project description:Background: Asthma is highly heterogeneous and severity evaluation is key to asthma management. DNA methylation (DNAm) contributes to asthma pathogenesis. This study aimed to identify nasal epithelial DNAm differences between severe and non-severe asthmatic children and evaluate the impact of environmental exposures. Methods: Thirty-three non-severe and 22 severe asthmatic African-American children were included in an epigenome-wide association study. Genome-wide nasal epithelial DNAm and gene expression were measured. CpG sites associated with asthma severity and environmental exposures and predictive of severe asthma were identified. DNAm was correlated with gene expression. Enrichment for transcription factor (TF) binding sites or histone modifications surrounding DNAm differences were determined. Results: We identified 816 differentially methylated CpG positions (DMPs) and 10 differentially methylated regions (DMRs) associated with asthma severity. Three DMPs exhibited discriminatory ability for severe asthma. Intriguingly, six DMPs were simultaneously associated with asthma, allergic asthma, total IgE, environmental IgE, and FeNO in an independent cohort of children. 27 DMPs were associated with traffic-related air pollution or secondhand smoke. DNAm at 22 DMPs were altered by diesel particles or allergen in human bronchial epithelial cells. DNAm levels at 39 DMPs were correlated with mRNA expression. Proximal to 816 DMPs, three histone marks and several TFs involved in asthma pathogenesis were enriched. Conclusions: Significant differences in nasal epithelial DNAm were observed between non-severe and severe asthma in African-American children, a subset of which may be useful to predict disease severity. These CpG sites are subject to the influences of environmental exposures and may regulate gene expression.
2022-04-15 | GSE161485 | GEO
Project description:An innovative, high-throughput approach was proposed to identify key gene expression profiles and regulatory polymorphisms affecting innate immunity to TB by studying interactions between M.tb and human alveolar macrophages (AMs). We systematically analyzed interactions of a virulent M.tb strain with freshly isolated human AMs from 28 healthy adult donors, measuring host RNA expression and secreted candidate proteins associated with TB pathogenesis over 72h. We observed large inter-individual differences in bacterial uptake and growth, with tenfold variation in M.tb load at 72h, reflected by large variation of gene expression programs. Systems analysis of differential and variable RNA and protein expression identifies TB-associated genes and networks (e.g., IL1B and IDO1). RNA time profiles document early stimulation of M1-type macrophage gene expression followed by emergence of an M2-type profile.
2023-08-07 | GSE189996 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial disease of unknown cause. It remains impractical to conduct early diagnosis and predict IPF progression just based on gene expression information. Moreover, the relationship between gene expression and quantitative phenotypic value in IPF keeps controversial. To identify biomarkers to predict survival in IPF, we profiled protein-coding gene expression in peripheral blood mononuclear cells (PBMCs). We linked the gene expression level with the quantitative phenotypic variation in IPF, including diffusing capacity of the lung for carbon monoxide (DLCO) and forced vital capacity (FVC) percent predicted. In silico analyses on the expression profiles and quantitative phenotypic data allowed for the generation of a set of IPF molecular signature that predicted survival of IPF effectively. Total RNA was isolated from PBMCs using standard molecular biology protocols without DNA contamination or RNA degradation. Sample processing (e.g., cDNA generation, fragmentation, end labeling, hybridization to Affymetrix GeneChip Human Exon 1.0 ST arrays) was performed per manufacturer’s instructions. A total of 45 healthy controls and 70 IPF patients were included in the microarray analysis.
2014-06-30 | E-GEOD-38958 | biostudies-arrayexpress
Project description:We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma versus healthy controls. We identified 119 differentially methylated regions (DMRs) and 118 differentially methylated probes (DMPs) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. Hypo- and hypermethylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma.
2015-11-01 | GSE65204 | GEO
Project description:Objectives: Idiopathic pulmonary fibrosis (IPF) is a complex disease in which a multitude of proteins and networks are disrupted. Interrogation of genome-wide transcription through RNA sequencing (RNA-Seq) enables the determination of genes whose differential expression is most significant in IPF, as well as the detection of alternative splicing events which are not easily observed with traditional microarray experiments. Methods: Messenger RNA extracted from 8 IPF lung samples and 7 healthy controls was sequenced on an Illumina HiSeq. Analysis of differential expression and exon usage was performed using Bioconductor packages. The gene periostin was selected for validation of alternative splicing by quantitative PCR, and pathway analysis was performed to determine enrichment for differentially expressed and spliced genes. Results: There were 873 genes differentially expressed in IPF (FDR 5%), and 440 unique genes had significant differential splicing events (FDR 5%). In particular, cassette exon 21 of the gene periostin was significantly more likely to be spliced out in IPF samples (adj pval = 2.06e-09), and this result was confirmed by qPCR (Wilcoxon pval = 3.11e-4). We also found that genes close to SNPs in the discovery set of a recent IPF GWAS were enriched for genes differentially expressed in our data, including genes like mucin5B and desmoplakin which have been previously associated with IPF. Conclusions: There is significant differential splicing and expression in IPF lung samples as compared with healthy controls. We found a strong signal of differential cassette exon usage in periostin, an extracellular matrix protein whose increased gene-level expression has been associated with IPF and its clinical progression, but for which differential splicing has not been studied in the context of IPF. Our results suggest that alternative splicing of periostin and other genes may be involved in the pathogenesis of IPF. mRNA sequencing of 8 IPF and 7 control lung tissue samples.
2014-03-27 | E-GEOD-52463 | biostudies-arrayexpress